The present invention relates to piperidine derivatives useful as selective CCR5 antagonists, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds. The invention also relates to the use of a combination of a CCR5 antagonist of this invention and one or more antiviral or other agents useful in the treatment of Human Immunodeficiency Virus (HIV). The invention further relates to the use of a CCR-5 antagonist of this invention, alone or in combination with another agent, in the treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis.
The global health crisis caused by HIV, the causative agent of Acquired Immunodeficiency Syndrome (AIDS), is unquestioned, and while recent advances in drug therapies have been successful in slowing the progression of AIDS, there is still a need to find a safer, more efficient, less expensive way to control the virus.
It has been reported that the CCR5 gene plays a role in resistance to HIV infection. HIV infection begins by attachment of the virus to a target cell membrane through interaction with the cellular receptor CD4 and a secondary chemokine co-receptor molecule, and proceeds by replication and dissemination of infected cells through the blood and other tissue. There are various chemokine receptors, but for macrophage-tropic HIV, believed to be the key pathogenic strain that replicates in vivo in the early stages of infection, the principal chemokine receptor required for the entry of HIV into the cell is CCR5. Therefore, interfering with the interaction between the viral receptor CCR5 and HIV can block HIV entry into the cell. The present invention relates to small molecules which are CCR5 antagonists.
CCR-5 receptors have been reported to mediate cell transfer in inflammatory diseases such as arthritis, rheumatoid arthritis, atopic dermatitis, psoriasis, asthma and allergies, and inhibitors of such receptors are expected to be useful in the treatment of such diseases, and in the treatment of other inflammatory diseases or conditions such as inflammatory bowel disease, multiple sclerosis, solid organ transplant rejection and graft v. host disease.
Related piperidine derivatives which are muscarinic antagonists useful in the treatment of cognitive disorders such as Alzheimer""s disease are disclosed in U.S. Pat. Nos. 5,883,096; 6,037,352; 5,889,006; 5,952,349; and 5,977,138.
A-M. Vandamme et al., Antiviral Chemistry and Chemotherapy, 9:187-203 (1998) disclose current clinical treatments of HIV-1 infections in man including at least triple drug combinations or so-called Highly Active Antiretroviral Therapy (xe2x80x9cHAARTxe2x80x9d); HAART involves various combinations of nucleoside reverse transcriptase inhibitors (xe2x80x9cNRTIxe2x80x9d), non-nucleoside reverse transcriptase inhibitors (xe2x80x9cNNRTIxe2x80x9d) and HIV protease inhibitors (xe2x80x9cPIxe2x80x9d). In compliant drug-naive patients, HAART is effective in reducing mortality and progression of HIV-1 to AIDS. However, these multidrug therapies do not eliminate HIV-1 and long-term treatment usually results in multidrug resistance. Development of new drug therapies to provide better HIV-1 treatment remains a priority.
The present invention relates to the treatment of HIV comprising administering to a human in need of such treatment an effective amount of a CCR5 antagonist represented by the structural formula I: 
or a pharmaceutically acceptable salt thereof, wherein 
R is R6-phenyl, R6-pyridyl, R6-thiophenyl or R6-naphthyl;
R1 is hydrogen, C1-C6 alkyl or C2-C6 alkenyl;
R2 is R7, R8, R9-phenyl; R7, R8, R9-substituted 6-membered heteroaryl; R7, R8, R9-substituted 6-membered heteroaryl N-oxide; R10, R11-substituted 5-membered heteroaryl; naphthyl; fluorenyl;
diphenylmethyl 
R3 is R6-phenyl, R6-heteroaryl or R6-naphthyl;
R4 is hydrogen, C1-C6 alkyl, fluoro-C1-C6 alkyl, cyclopropylmethyl, xe2x80x94CH2CH2OH, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94(C1-C6)alkyl, xe2x80x94CH2C(O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, xe2x80x94CH2C(O)NH2, xe2x80x94CH2C(O)xe2x80x94NH(C1-C6)alkyl or xe2x80x94CH2C(O)xe2x80x94N((C1-C6)alkyl)2;
R5 and R11 are independently selected from the group consisting of hydrogen and (C1-C6)-alkyl;
R6 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94CF3, CF3Oxe2x80x94, CH3C(O)xe2x80x94, xe2x80x94CN, CH3SO2xe2x80x94, CF3SO2xe2x80x94, R14-phenyl, R14-benzyl, CH3C(xe2x95x90NOCH3)xe2x80x94, CH3C(xe2x95x90NOCH2CH3)xe2x80x94, 
xe2x80x94NHCONH(C1-C6alkyl), xe2x80x94NHCO(C1-C6alkyl), xe2x80x94NHSO2(C1-C6alkyl), 5-membered heteroaryl and 
wherein X is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94N(CH3)xe2x80x94;
R7 and R8 are independently selected from the group consisting of (C1-C6)alkyl, halogen, xe2x80x94NR20R21, xe2x80x94OH, xe2x80x94CF3, xe2x80x94OCH3, xe2x80x94O-acyl, and xe2x80x94OCF3;
R9 is R7, hydrogen, phenyl, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CH2F, xe2x80x94CHF2, xe2x80x94CHO, xe2x80x94CHxe2x95x90NOR20, pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, xe2x80x94N(R20)CONR21R22, xe2x80x94NHCONH(chloro-(C1-C6)alkyl), xe2x80x94NHCONH((C3-C10)-cycloalkyl (C1-C6)alkyl), xe2x80x94NHCO(C1-C6)alkyl, xe2x80x94NHCOCF3, xe2x80x94NHSO2N((C1-C6)alkyl)2, xe2x80x94NHSO2(C1-C6)alkyl, xe2x80x94N(SO2CF3)2, xe2x80x94NHCO2(C1-C6)alkyl, C3-C10cycloalkyl, xe2x80x94SR23, xe2x80x94SOR23, xe2x80x94SO2R23, xe2x80x94SO2NH(C1-C6alkyl), xe2x80x94OSO2(C1-C6)alkyl, xe2x80x94OSO2CF3, hydroxy(C1-C6)alkyl, xe2x80x94CON R21R20, xe2x80x94CON(CH2CH2xe2x80x94Oxe2x80x94CH3)2, xe2x80x94OCONH(C1-C6)alkyl, xe2x80x94CO2R20, xe2x80x94Si(CH3)3 or xe2x80x94B(OC(CH3)2)2;
R10 is (C1-C6)alkyl, xe2x80x94NH2 or R12-phenyl;
R12 is 1 to 3 substituents independently selected from the group consisting of hydrogen, (C1-C6) alkyl, xe2x80x94CF3, xe2x80x94CO2R20, xe2x80x94CN, (C1-C6)alkoxy and halogen;
R13, R14, R15 and R16 are independently selected from the group consisting of hydrogen and (C1-C6)alkyl;
R17 and R18 are independently selected from the group consisting of hydrogen and C1-C6 alkyl, or R17 and R18 together are a C2-C5 alkylene group and with the carbon to which they are attached form a spiro ring of 3 to 6 carbon atoms;
R19 is R6-phenyl, R6-heteroaryl, R6-naphthyl, C3-C1 cycloalkyl, (C3-C10)cycloalkyl(C1-C6)alkyl or (C1-C6)alkoxy(C1-C6)alkyl;
R20, R21 and R22 are independently selected from the group consisting of H and C1-C6 alkyl; and
R23 is C1-C6 alkyl or phenyl.
Preferred are compounds of formula I wherein R is R6-phenyl, especially wherein R6 is a single substituent, and especially wherein the R6 substituent is in the 4-position. Also preferred are compounds of formula I wherein R13, R14, R15 and R16 are each hydrogen or methyl, especially hydrogen. Also preferred are compounds of formula I wherein X is xe2x80x94CHOR3, xe2x80x94C(R13)(R19)xe2x80x94 or xe2x80x94C(xe2x95x90NOR4)xe2x80x94; a preferred definition for R3 is pyridyl, especially 2-pyridyl, a preferred definition for R4 is (C1-C6)alkyl, especially methyl, ethyl or isopropyl, a preferred definition for R13 is hydrogen, and a preferred definition for R19 is R6-phenyl. For compounds of formula I, R1 is preferably (C1-C6)alkyl, especially methyl.
In compounds of formula I, R2 is preferably R7, R8, R9-phenyl, R7, R8, R9-pyridyl or an N-oxide thereof, or R7, R8, R9-pyrimidyl. When R2 is pyridyl, it is preferably 3- or 4-pyridyl, and when pyrimidyl, it is preferably 5-pyrimidyl. The R7 and R8 substituents are preferably attached to carbon ring members adjacent to the carbon joining the ring to the rest of the molecule and the R9 substituent can be attached to any of the remaining unsubstituted carbon ring members, for example as shown in the following structures: 
Preferred R7 and R8 substituents are: (C1-C6)alkyl, especially methyl; halogen, especially chloro; and xe2x80x94NH2. A preferred R9 substituent is hydrogen.
Also claimed are novel CCR5 antagonist compounds represented by the structural formula II 
or a pharmaceutically acceptable salt thereof, wherein 
Ra is R6a-phenyl, R6a-pyridyl, R6a-thiophenyl or R6-naphthyl;
R1 is hydrogen, C1-C6 alkyl or C2-C6 alkenyl;
R2 is R7, R8, R9-phenyl; R7, R8, R9-substituted 6-membered heteroaryl; R7, R8, R9-substituted 6-membered heteroaryl N-oxide; R10, R11-substituted 5-membered heteroaryl; naphthyl; fluorenyl; diphenylmethyl 
R3 is R10-phenyl, pyridyl, pyrimidyl, pyrazinyl or thiazolyl;
R4 is hydrogen, C1-C6 alkyl, fluoro-C1-C6 alkyl, cyclopropylmethyl, xe2x80x94CH2CH2OH, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94(C1-C6)alkyl, xe2x80x94CH2C(O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, xe2x80x94CH2C(O)NH2, xe2x80x94CH2C(O)xe2x80x94NH(C1-C6)alkyl or xe2x80x94CH2C(O)xe2x80x94N((C1-C6)alkyl)2;
R5 and R11 are independently selected from the group consisting of hydrogen and (C1-C6)-alkyl;
R6a is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, xe2x80x94CF3, CF3Oxe2x80x94, xe2x80x94CN, xe2x80x94CF3SO2xe2x80x94, R12-phenyl, xe2x80x94NHCOCF3, 5-membered heteroaryl and 
wherein X is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94N(CH3)xe2x80x94;
R6 is independently selected from the group consisting of R6a and CH3SO2xe2x80x94;
R7 and R8 are independently selected from the group consisting of (C1-C6)alkyl, halogen, xe2x80x94NR20R21, xe2x80x94OH, xe2x80x94CF3, xe2x80x94OCH3, xe2x80x94O-acyl, and xe2x80x94OCF3;
R9 is R7, hydrogen, phenyl, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CH2F, xe2x80x94CHF2, xe2x80x94CHO, xe2x80x94CHxe2x95x90NOR20, pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, xe2x80x94N(R20)CONR21R22, xe2x80x94NHCONH(chloro-(C1-C6)alkyl), xe2x80x94NHCONH((C3-C10)-cycloalkyl(C1-C6)alkyl), xe2x80x94NHCO(C1-C6)alkyl, xe2x80x94NHCOCF3, xe2x80x94NHSO2N((C1-C6)alkyl)2, xe2x80x94NHSO2(C1-C6)alkyl, xe2x80x94N(SO2CF3)2, xe2x80x94NHCO2(C1-C6)alkyl, C3-C10 cycloalkyl, xe2x80x94SR23, xe2x80x94SOR23, xe2x80x94SO2R23, xe2x80x94SO2NH(C1-C6alkyl), xe2x80x94OSO2(C1-C6)alkyl, xe2x80x94OSO2CF3, hydroxy(C1-C6)alkyl, xe2x80x94CON R20R21, xe2x80x94CON(CH2CH2xe2x80x94Oxe2x80x94CH3)2, xe2x80x94OCONH(C1-C6)alkyl, xe2x80x94CO2R20, xe2x80x94Si(CH3)3 or xe2x80x94B(OC(CH3)2)2;
R10 is (C1-C6)alkyl, xe2x80x94NH2 or R12-phenyl;
R12 is 1 to 3 substituents independently selected from the group consisting of hydrogen, (C1-C6)alkyl, xe2x80x94CF3, xe2x80x94CO2R20, xe2x80x94CN, (C1-C6)alkoxy and halogen;
R13, R14, R15 and R16 are independently selected from the group consisting of hydrogen and (C1-C6)alkyl;
R17 and R18 are independently selected from the group consisting of hydrogen and C1-C6 alkyl, or R17 and R18 together are a C2-C5 alkylene group and with the carbon to which they are attached form a spiro ring of 3 to 6 carbon atoms;
R19 is R6-phenyl, R6-heteroaryl, R6-naphthyl, C3-C10cycloalkyl, (C3-C10)cycloalkyl(C1-C6)alkyl or (C1-C6)alkoxy(C1-C6)alkyl;
R20, R21 and R22 are independently selected from the group consisting of H and C1-C6 alkyl; and
R23 is C1-C6 alkyl or phenyl; or (2): 
Ra is R6b-phenyl, R6b-pyridyl or R6b-thiophenyl;
R4a is fluoro-C1-C6 alkyl, cyclopropylmethyl, xe2x80x94CH2CH2OH, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94(C1-C6)alkyl, xe2x80x94CH2C(O)xe2x80x94Oxe2x80x94(C1 -C6)alkyl, xe2x80x94CH2C(O)NH2, xe2x80x94CH2C(O)xe2x80x94NHxe2x80x94(C1-C6)alkyl or xe2x80x94CH2C(O)xe2x80x94N((C1-C6)alkyl)2;
R6b is CH3SO2xe2x80x94; and
R1, R2, R3, R5, R14, R15, R16 and R19 are as defined in (1).
Preferred are compounds of formula II(1) wherein Ra is R6a-phenyl, especially wherein R6a is a single substituent, and especially wherein the R6a substituent is in the 4-position. Also preferred are compounds of formula II(1) wherein Xa is xe2x80x94CHOR3, xe2x80x94C(R13)(R19)xe2x80x94 or xe2x80x94C(xe2x95x90NOR4)xe2x80x94; a preferred definition for R3 is pyridyl, especially 2-pyridyl, a preferred definition for R4 is (C1-C6)alkyl, especially methyl, ethyl or isopropyl, a preferred definition for R13 is hydrogen, and a preferred definition for R19 is R6-phenyl. For compounds of formula II(1), R1 is preferably (C1-C6)alkyl,
Preferred are compounds of formula II(2) wherein Ra is R6b-phenyl, especially wherein R6b is a single substituent, and especially wherein the R6b substituent is in the 4-position. Also preferred are compounds of formula II(2) wherein Xa is xe2x80x94CHOR3, xe2x80x94C(R13)(R19)xe2x80x94 or xe2x80x94C(xe2x95x90NOR4a)xe2x80x94; a preferred definition for R3 is pyridyl, especially 2-pyridyl, preferred definitions for R4a are cyclopropylmethyl and trifluoroethyl, a preferred definition for R13 is hydrogen, and a preferred definition for R19 is R6-phenyl. For compounds of formula II(2), R1 is preferably (C1-C6)alkyl, especially methyl. Also for compounds of formula II(2), R14, R15 and R16 are preferably hydrogen.
In compounds of formula II(1) and (2), R2 is preferably R7, R8, R9-phenyl; R7, R8, R9-pyridyl or an N-oxide thereof; or R7, R8, R9-pyrimidyl. When R2 is pyridyl, it is preferably 3- or 4-pyridyl, and when pyrimidyl, it is preferably 5-pyrimidyl. The R7 and R8 substituents are preferably attached to carbon ring members adjacent to the carbon joining the ring to the rest of the molecule and the R9 substituent can be attached to any of the remaining unsubstituted carbon ring members as shown above for compounds of formula I. Preferred R7 and R8 substituents for compounds of formula II are: (C1-C6)alkyl, especially methyl; halogen, especially chloro; and xe2x80x94NH2; a preferred R9 substituent is hydrogen.
Another aspect of the invention is a pharmaceutical composition for treatment of HIV comprising an effective amount of a CCR5 antagonist of formula II in combination with a pharmaceutically acceptable carrier. Another aspect of the invention is a pharmaceutical composition for treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis comprising an effective amount of a CCR5 antagonist of formula II in combination with a pharmaceutically acceptable carrier.
Yet another aspect of this invention is a method of treatment of HIV comprising administering to a human in need of such treatment an effective amount of a CCR5 antagonist compound of formula II. Another aspect of the invention is a method of treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis comprising administering to a human in need of such treatment an effective amount of a CCR5 antagonist compound of formula I or II. comprising administering to a human in need of such treatment an effective amount of a CCR5 antagonist compound of formula I or II.
Still another aspect of this invention is the use of a CCR5 antagonist of formula I or II of this invention in combination with one or more antiviral or other agents useful in the treatment of Human Immunodeficiency Virus for the treatment of AIDS. Still another aspect of this invention is the use of a CCR5 antagonist of formula I or II of this invention in combination with one or more other agents useful in the treatment of solid organ transplant rejection, graft v. host disease, inflammatory bowel disease, rheumatoid arthritis or multiple sclerosis. The CCR5 and antiviral or other agents which are components of the combination can be administered in a single dosage form or they can be administered separately; a kit comprising separate dosage forms of the actives is also contemplated.
As used herein, the following terms are used as defined below unless otherwise indicated.
Alkyl (including the alkyl portions of alkoxy, alkylamino and dialkylamino) represents straight and branched carbon chains and contains from one to six carbon atoms.
Alkenyl represents C2-C6 carbon chains having one or two unsaturated bonds, provided that two unsaturated bonds are not adjacent to each other.
Substituted phenyl means that the phenyl group can be substituted at any available position on the phenyl ring.
Acyl means a radical of a carboxylic acid having the formula alkyl-C(O)xe2x80x94, aryl-C(O)xe2x80x94, aralkyl-C(O)xe2x80x94, (C3-C7)cycloalkyl-C(O)xe2x80x94, (C3-C7)cycloalkyl-(C1-C6)alkyl-C(O)xe2x80x94, and heteroaryl-C(O)xe2x80x94, wherein alkyl and heteroaryl are as defined herein; aryl is R12-phenyl or R12-naphthyl; and aralkyl is aryl-(C1-C6)alkyl, wherein aryl is as defined above.
Heteroaryl represents cyclic aromatic groups of 5 or 6 atoms or bicyclic groups of 11 to 12 atoms having 1 or 2 heteroatoms independently selected from O, S or N, said heteroatom(s) interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, provided that the rings do not contain adjacent oxygen and/or sulfur atoms. For 6-membered heteroaryl rings, carbon atoms can be substituted by R7, R8 or R9 groups. Nitrogen atoms can form an N-oxide. All regioisomers are contemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl. Typical 6-membered heteroaryl groups are pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and the N-oxides thereof. For 5-membered heteroaryl rings, carbon atoms can be substituted by R10 or R11 groups. Typical 5-membered heteroaryl rings are furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl and isoxazolyl. 5-Membered rings having one heteroatom can be joined through the 2- or 3-position; 5-membered rings having two heteroatoms are preferably joined through the 4-position. Bicyclic groups typically are benzo-fused ring systems derived from the heteroaryl groups named above, e.g. quinolyl, phthalazinyl, quinazolinyl, benzofuranyl, benzothienyl and indolyl.
Preferred points of substitution for 6-membered heteroaryl rings at R2 are described above. When R2 is a 5-membered heteroaryl group, the R10 and R11 substituents are preferably attached to carbon ring members adjacent to the carbon joining the ring to the rest of the molecule, and R11 is preferably alkyl; however, if a heteroatom is adjacent to the carbon joining the ring to the rest of the molecule (i.e., as in 2-pyrrolyl), R10 is preferably attached to a carbon ring member adjacent to the carbon joining the ring to the rest of the molecule.
Halogen represents fluoro, chloro, bromo and iodo.
Fluoro(C1-C6)alkyl represents a straight or branched alkyl chain substituted by 1 to 5 fluoro atoms, which can be attached to the same or different carbon atoms, e.g., xe2x80x94CH2F, xe2x80x94CHF2, xe2x80x94CF3, F3CCH2xe2x80x94 and xe2x80x94CF2CF3.
A therapeutically effective amount of a CCR5 antagonist is an amount sufficient to lower HIV-1-RNA plasma levels.
One or more, preferably one to four, antiviral agents useful in anti-HIV-1 therapy may be used in combination with a CCR5 antagonist of the present invention. The antiviral agent or agents may be combined with the CCR5 antagonist in a single dosage form, or the CCR5 antagonist and the antiviral agent or agents may be administered simultaneously or sequentially as separate dosage forms. The antiviral agents contemplated for use in combination with the compounds of the present invention comprise nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and other antiviral drugs listed below not falling within these classifications. In particular, the combinations known as HAART are contemplated for use in combination with the CCR5 antagonists of this invention.
The term xe2x80x9cnucleoside and nucleotide reverse transcriptase inhibitorsxe2x80x9d (xe2x80x9cNRTIxe2x80x9ds) as used herein means nucleosides and nucleotides and analogues thereof that inhibit the activity of HIV-1 reverse transcriptase, the enzyme which catalyzes the conversion of viral genomic HIV-1 RNA into proviral HIV-1 DNA.
Typical suitable NRTIs include zidovudine (AZT) available under the RETROVIR tradename from Glaxo-Wellcome Inc., Research Triangle, N.C. 27709; didanosine (ddl) available under the VIDEX tradename from Bristol-Myers Squibb Co., Princeton, N.J. 08543; zalcitabine (ddC) available under the HIVID tradename from Roche Pharmaceuticals, Nutley, N.J. 07110; stavudine (d4T) available under the ZERIT trademark from Bristol-Myers Squibb Co., Princeton, N.J. 08543; lamivudine (3TC) available under the EPIVIR tradename from Glaxo-Wellcome Research Triangle, N.C. 27709; abacavir (1592U89) disclosed in WO96/30025 and available under the ZIAGEN trademark from Glaxo-Wellcome Research Triangle, N.C. 27709; adefovir dipivoxil [bis(POM)-PMEA] available under the PREVON tradename from Gilead Sciences, Foster City, Calif. 94404; lobucavir (BMS-180194), a nucleoside reverse transcriptase inhibitor disclosed in EP-0358154 and EP-0736533 and under development by Bristol-Myers Squibb, Princeton, N.J. 08543; BCH-10652, a reverse transcriptase inhibitor (in the form of a racemic mixture of BCH-10618 and BCH-10619) under development by Biochem Pharma, Laval, Quebec H7V, 4A7, Canada; emitricitabine [(xe2x88x92)-FTC] licensed from Emory University under Emory Univ. U.S. Pat. No. 5,814,639 and under development by Triangle Pharmaceuticals, Durham, N.C. 27707; beta-L-FD4 (also called beta-L-D4C and named beta-L-2xe2x80x2, 3xe2x80x2-dicleoxy-5-fluoro-cytidene) licensed by Yale University to Vion Pharmaceuticals, New Haven Conn. 06511; DAPD, the purine nucleoside, (xe2x88x92)-beta-D-2,6,-diamino-purine dioxolane disclosed in EP-0656778 and licensed by Emory University and the University of Georgia to Triangle Pharmaceuticals, Durham, N.C. 27707; and lodenosine (FddA), 9-(2,3-dideoxy-2-fluoro-b-D-threo-pentofuranosyl)adenine, an acid stable purine-based reverse transcriptase inhibitor discovered by the NIH and under development by U.S. Bioscience Inc., West Conshohoken, Pa. 19428.
The term xe2x80x9cnon-nucleoside reverse transcriptase inhibitorsxe2x80x9d (xe2x80x9cNNRTIxe2x80x9ds) as used herein means non-nucleosides that inhibit the activity of HIV-1 reverse transcriptase.
Typical suitable NNRTIs include nevirapine (BI-RG-587) available under the VIRAMUNE tradename from Boehringer Ingelheim, the manufacturer for Roxane Laboratories, Columbus, Ohio 43216; delaviradine (BHAP, U-90152) available under the RESCRIPTOR tradename from Pharmacia and Upjohn Co., Bridgewater N.J. 08807; efavirenz (DMP-266) a benzoxazin-2-one disclosed in WO94/03440 and available under the SUSTIVA tradename from DuPont Pharmaceutical Co., Wilmington, Del. 19880-0723; PNU-142721, a furopyridine-thio-pyrimide under development by Pharmacia and Upjohn, Bridgewater N.J. 08807; AG-1549 (formerly Shionogi # S-1153); 5-(3,5-dichlorophenyl)-thio-4-isopropyl-1-(4-pyridyl)methyl-1H-imidazol-2-ylmethyl carbonate disclosed in WO 96/10019 and under clinical development by Agouron Pharmaceuticals, Inc., LaJolla Calif. 92037-1020; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione) discovered by Mitsubishi Chemical Co. and under development by Triangle Pharmaceuticals, Durham, N.C. 27707; and (+)-calanolide A (NSC-675451) and B, coumarin derivatives disclosed in NIH U.S. Pat. No. 5,489,697, licensed to Med Chem Research, which is co-developing (+) calanolide A with Vita-invest as an orally administrable product.
The term xe2x80x9cprotease inhibitorxe2x80x9d (xe2x80x9cPIxe2x80x9d) as used herein means inhibitors of the HIV-1 protease, an enzyme required for the proteolytic cleavage of viral polyprotein precursors (e.g., viral GAG and GAG Pol polyproteins), into the individual functional proteins found in infectious HIV-1. HIV protease inhibitors include compounds having a peptidomimetic structure, high molecular weight (7600 daltons) and substantial peptide character, e.g. CRIXIVAN(available from Merck) as well as nonpeptide protease inhibitors e.g., VIRACEPT (available from Agouron).
Typical suitable PIs include saquinavir (Ro 31-8959) available in hard gel capsules under the INVIRASE tradename and as soft gel capsules under the FORTOVASE tradename from Roche Pharmaceuticals, Nutley, N.J. 07110-1199; ritonavir (ABT-538) available under the NORVIR tradename from Abbott Laboratories, Abbott Park, Ill. 60064; indinavir (MK-639) available under the CRIXIVAN tradename from Merck and Co., Inc., West Point, Pa. 19486-0004; nelfnavir (AG-1343) available under the VIRACEPT tradename from Agouron Pharmaceuticals, Inc., LaJolla Calif. 92037-1020; amprenavir (141W94), tradename AGENERASE, a non-peptide protease inhibitor under development by Vertex Pharmaceuticals, Inc., Cambridge, Mass. 02139-4211 and available from Glaxo-Wellcome, Research Triangle, N.C. under an expanded access program; lasinavir (BMS-234475) available from Bristol-Myers Squibb, Princeton, N.J. 08543 (originally discovered by Novartis, Basel, Switzerland (CGP-61755); DMP-450, a cyclic urea discovered by Dupont and under development by Triangle Pharmaceuticals; BMS-2322623, an azapeptide under development by Bristol-Myers Squibb, Princeton, N.J. 08543, as a 2nd-generation HIV-1 PI; ABT-378 under development by Abbott, Abbott Park, Ill. 60064; and AG-1549 an orally active imidazole carbamate discovered by Shionogi (Shionogi #S-1153) and under development by Agouron Pharmaceuticals, Inc., LaJolla Calif. 92037-1020.
Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No. 11607. Hydroyurea (Droxia), a ribonucleoside triphosphate reductase inhibitor, the enzyme involved in the activation of T-cells, was discovered at the NCI and is under development by Bristol-Myers Squibb; in preclinical studies, it was shown to have a synergistic effect on the activity of didanosine and has been studied with stavudine. IL-2 is disclosed in Ajinomoto EP-0142268, Takeda EP-0176299, and Chiron U.S. Pat. Nos. RE 33,653, 4,530,787, 4,569,790, 4,604,377, 4,748,234, 4,752,585, and 4,949,314, and is available under the PROLEUKIN (aldesleukin) tradename from Chiron Corp., Emeryville, Calif. 94608-2997 as a lyophilized powder for IV infusion or sc administration upon reconstitution and dilution with water; a dose of about 1 to about 20 million 1U/day, sc is preferred; a dose of about 15 million 1 U/day, sc is more preferred. IL-12 is disclosed in WO96/25171 and is available from Roche Pharmaceuticals, Nutley, N.J. 07110-1199 and American Home Prodocts, Madison, N.J. 07940; a dose of about 0.5 microgram/kg/day to about 10 microgram/kg/day, sc is preferred. Pentafuside (DP-178, T-20) a 36-amino acid synthetic peptide, disclosed in U.S. Pat. No. 5,464,933 licensed from Duke University to Trimeris which is developing pentafuside in collaboration with Duke University; pentafuside acts by inhibiting fusion of HIV-1 to target membranes. Pentafuside (3-100 mg/day) is given as a continuous sc infusion or injection together with efavirenz and 2 PI""s to HIV-1 positive patients refractory to a triple combination therapy; use of 100 mg/day is preferred. Yissum Project No. 11607, a synthetic protein based on the HIV-1 Vif protein, is under preclinical development by Yissum Research Development Co., Jerusalem 91042, Israel. Ribavirin, 1-xcex2-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, is available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif.; its manufacture and formulation are described in U.S. Pat. No. 4,211,771.
The term xe2x80x9canti-HIV-1 therapyxe2x80x9d as used herein means any anti-HIV-1 drug found useful for treating HIV-1 infections in man alone, or as part of multidrug combination therapies, especially the HAART triple and quadruple combination therapies. Typical suitable known anti-HIV-1 therapies include, but are not limited to multidrug combination therapies such as (i) at least three anti-HIV-1 drugs selected from two NRTIs, one PI, a second PI, and one NNRTI; and (ii) at least two anti-HIV-1 drugs selected from NNRTIs and PIs. Typical suitable HAARTxe2x80x94multidrug combination therapies include:
(a) triple combination therapies such as two NRTIs and one PI; or (b) two NRTIs and one NNRTI; and (c) quadruple combination therapies such as two NRTIs, one PI and a second PI or one NNRTI. In treatment of naive patients, it is preferred to start anti-HIV-1 treatment with the triple combination therapy; the use of two NRTIs and one PI is preferred unless there is intolerance to PIs. Drug compliance is essential. The CD4+ and HIV-1-RNA plasma levels should be monitored every 3-6 months. Should viral load plateau, a fourth drug, e.g., one PI or one NNRTI could be added. See the table below wherein typical therapies are further described:
A. Triple Combination Therapies
1. Two NRTIs1+one PI2 
2. Two NRTIs1+one NNRTI3 
B. Quadruple Combination Therapies4 
Two NRTIs+one PI+a second PI or one NNRTI
C. ALTERNATIVES:5 
Two NRTI1 
One NRTI5+one PI2 
Two PIs6xc2x1one NRTI7 or NNRTI3 
One PI2+one NRTI7+one NNRTI3 
1. One of the following: zidovudine+lamivudine; zidovudine+didanosine; stavudine+lamivudine; stavudine+didanosine; zidovudine+zalcitabine
2. Indinavir, nelfinavir, ritonavir or saquinavir soft gel capsules.
3. Nevirapine or delavirdine.
4. See A-M. Vandamne et al Antiviral Chemistry and Chemotherapy 9:187 at p 193-197 and FIGS. 1-2. who fail or relapse on a recommended regimen. Double nucleoside combinations may lead to HIV-resistance and clinical failure in many patients.
6. Most data obtained with saquinavir and ritonavir (each 400 mg bid).
7. Zidovudine, stavudine or didanosine.
Agents known in the treatment of rheumatoid arthritis, transplant and graft v. host disease, inflammatory bowel disease and multiple sclerosis which can be administered in combination with the CCR5 antagonists of the present invention are as follows:
solid organ transplant rejection and graft v. host disease: immune suppressants such as cyclosporine and Interleukin-10 (IL-10), tacrolimus, antilymphocyte globulin, OKT-3 antibody, and steroids;
inflammatory bowel disease: IL-10 (see U.S. Pat. No. 5,368,854), steroids and azulfidine;
rheumatoid arthritis: methotrexate, azathioprine, cyclophosphamide, steroids and mycophenolate mofetil;
multiple sclerosis: interferon-beta, interferon-alpha, and steroids.
Certain CCR5 antagonist compounds of the invention may exist in different isomeric (e.g., enantiomers, diastereoisomers and atropisomers) forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures.
Certain compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
Certain basic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.
All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Compounds of the invention can be made by the procedures known in the art, for example by the procedures described in the following reaction schemes, by the methods described in the examples below, and by using the methods described in U.S. Pat. Nos. 5,883,096; 6,037,352; 5,889,006; 5,952,349; and 5,977,138.
The following solvents and reagents may be referred to herein by the abbreviations indicated: tetrahydrofuran (THF); ethanol (EtOH); methanol (MeOH); acetic acid (HOAc or AcOH); ethyl acetate (EtOAc); N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA); trifluoroacetic anhydride (TFAA); 1-hydroxy-benzotriazole (HOBT); m-chloroperbenzoic acid (MCPBA); triethylamine (Et3N); diethyl ether (Et2O); tert-butoxy-carbonyl (BOC); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); dimethyl-sulfoxide (DMSO); p-toluene sulfonic acid (p-TSA); potassium bis(trimethylsilyl)-amide (KHMDA); 4-dimethylaminopryidine (DMAP); N,N,N-diiospropylethylamine (Dipea); and 1-(3-dimethyl-aminopropyl)-3-ethyl carbodiimide hydrochloride (DEC). RT is room temperature.
Compounds of formula I and II wherein X is CHO(Cxe2x95x90O)xe2x80x94(C1-C6)-alkyl, CHO(Cxe2x95x90O)xe2x80x94(C1-C6)alkoxy, CHO(Cxe2x95x90O)xe2x80x94NHxe2x80x94(C1-C6)alkyl, CHNR5(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, CHNR5(Cxe2x95x90O)xe2x80x94(C1-C6)alkoxy, CHNR5(Cxe2x95x90O)xe2x80x94NHxe2x80x94(C1-C6)alkyl or xe2x80x94CHOR3 (and wherein R14, R15 and R16 are hydrogen) are prepared according to Schemes 1-4:
Compounds of formula 3, wherein R, R7 and R8 are as defined for formula I, Z is CH or N, and R1 is an alkyl group such as methyl were prepared as depicted in Scheme 1. Ketone 1, the synthesis of which was described in WO98/05292, was subjected to standard amidation with ArCOOH, EDCI or DEC, and HOBT, or ArCOCI, wherein Ar is R7, R8-substituted phenyl or pyridyl, followed by reduction with NaBH4 to obtain 3. Derivatization of the free hydroxyl moiety with alkyl halides, acyl chlorides (R3COCl), alkyl chloroformates (CICOOR3) and isocyanides (Oxe2x95x90Cxe2x95x90NR3) afforded ethers 4a, esters 4b, carbonates 4c, and carbamates 4d, respectively, wherein R3 is a lower alkyl group. The aryloxy compounds, 5, were obtained after condensation of the hydroxyl 3 with phenyl or pyridyl halides in the presence of a base. 
Alternatively, compounds of formula 5 can be prepared by reduction of the N-Boc ketone 1a to the alcohol 6 first, followed by functionalization of the free hydroxyl group with a halogen-substituted aryl in the presence of a base as shown in Scheme 2, or by a hydroxy-substituted aryl or heteroaryl (wherein Z1 is as defined in Scheme 1) in the presence of PPh3 and an azodicarboxylate of the formula R19O2Cxe2x80x94Nxe2x95x90Nxe2x80x94CO2R20, wherein R20 is C1-C6 lower alkyl. Removal of the Boc protecting group and conversion to the amide is performed as in Scheme 1. This route allows the introduction of various aryloxy and heteroaryloxy moieties at R3 through the use of nucleophilic displacement or Mitsunobu-type reaction on intermediate 6.
Compounds of formula 8, wherein R, R1, R7, R8 and Z are as described in Scheme 1, were prepared by conversion of the ketone 2 to an oxime group with CH3ONH2.HCl, and reduction with BH3.S(CH3)2 to provide amine 8. Derivatization of the free amine moiety with an alkyl chloroformate (CICOOR20, wherein R20 is C1-C6 alkyl) or an isocyanide (Oxe2x95x90Cxe2x95x90NR3) affords carbamate compounds 9 and urea compounds 10, respectively. 
Preparation of chiral analogs was performed through chemical resolution. The alcohol 6 was coupled with a chiral Boc-protected amino acid to obtain diastereoisomers 11a and 11b which were separated by chromatography. The chiral auxialiary was then removed with NaOH for each diastereoisomer and the same sequence of reactions described in Scheme 2 was carried out on each individual enantiomer to obtain compounds 12a and 12b.
Oximes of formula I or II wherein X is Cxe2x95x90NOR4 are prepared from the corresponding ketones from any of several methods known to those skilled in the art. 
In Scheme 5, the ketone 1a, wherein R and R1 are as defined for formula I and II, is dissolved in a solvent such as CH3OH or ethanol and treated with an R4-substituted hydroxylamine such as O-methylhydroxyl-amine hydrochloride in the presence of a base such as sodium acetate. The resulting mixture of Z- and E-O-substituted oximes 13 can be separated or the mixture carried through and separated at the end. The BOC protecting group is removed by treatment with an acid such as aqueous HCl or trifluoroacetic acid, and the resulting amine is coupled to an acid under standard conditions to obtain a compound of formula I or II. 
Alternatively, the ketone 1a can be treated with HONH2.HCl under similar conditions to yield, after separation, the E- and Z-oximes. Each oxime is then treated with a base such as potassium hexamethyidisilazide in a suitable solvent such as DMF followed by treatment with an alkylating agent, e.g., CH3l, dimethylsulfate, CH3CH2l, trifluoroethyl triflate or similar electrophiles, to yield the desired O-substituted oxime.
The ketone starting material of formula 1a can be prepared by known methods as shown in Schemes 7 and 8.
In Scheme 7, Friedel-Crafts condensation of N-trifluoroacetyl-isonipecotoyl chloride 17 and an aromatic group R-H in the presence of a suitable catalyst such as AlCl3 and optionally in a solvent such as CH2Cl2 yields a ketone 18 which is converted to its ethylene ketal 19 under standard conditions. The N-trifluoroacetyl group is removed and the resulting free amine 20 is treated with N-BOC-piperidine-4-one in the presence of a dehydrating agent such as titanium isopropoxide followed by treatment with diethylaluminum cyanide to give an aminonitrile 21. The aminonitrile is treated with a grignard reagent (R1 Mg-halide) such as CH3MgBr or vinylmagnesium bromide to give the alkylated product 22. The ketal is removed by treatment with aqueous acid followed by re-protection under standard conditions using BOC anhydride to give 1a. 
Alternatively, 23, prepared via Wittig olefination of N-BOC-piperidone (Chen et al, Tetrahedron Lett., 37, 30 (1996), 5233-5234), is transformed to intermediate 25 by analogy to the procedure described in Scheme 7.25 is converted to alcohol 26 by hydroboration/oxidation. Alcohol 26 is treated with a suitable oxidant such as a mixture tetrapropylammonium perruthenate (TPAP) and N-methylmorpholine N-oxide (NMO) to give aldehyde 27. The aldehyde is treated with an aryllithium reagent in a suitable solvent such as ether or THF and the resulting alcohol 28 is treated with an oxidizing agent such as Dess-Martin periodinane or TPAP/NMO to give the desired ketone.
Compounds of formula I or II wherein X is xe2x80x94C(R13)(R19)xe2x80x94, wherein R and R19 are the same, or wherein R and R19 are different are prepared according to schemes 9 and 10, respectively. The schemes are exemplified by processes wherein R and R19 are each phenyl and wherein R is phenyl and R19 is CF3-phenyl, respectively, but the general procedures apply to other R and R19 groups. 
N-BOC-4-piperidone is treated with CBr4 to obtain the di-bromo compound of formula 44, which is then treated with phenylboronic acid to obtain the BOC-protected diphenylmethylene-piperidine of formula 45. The methylene bond is reduced using standard conditions to obtain the BOC-protected diphenylmethyl-piperidine of formula 46, the BOC group is removed and the amine of formula 47 is treated as described for compounds 20-22 of Scheme 7, the BOC group is removed by treatment with TFA, and the resultant amine subjected to a standard amidation procedure, e.g., treatment with a reagent R2COOH and coupling agents such as EDCI, HOBT and a base, to obtain the compounds of formula 48.
N-BOC-4-piperidone is treated with a reagent such as diethyl benzylphosphonate to obtain the phenylmethylene-piperidine of formula 49, which is then brominated to obtain the bromophenylmethylene-piperidine of fomula 50. The BOC protecting group is removed using standard conditions, e.g., treatment with TFA, to obtain amine 51, and the amine 51 is treated as described for compounds 20-22 of Scheme 7 to obtain the aminonitrile 52, then the protected amine 53. The amine 53 is treated with a reagent such as 4-CF3-phenylboronic acid to obtain compound 54 and the methylene bond is reduced using standard conditions to obtain racemic 55. The BOC group is removed by treatment with TFA, and the resultant amine subjected to a standard amidation procedure, e.g., treatment with a reagent R2COOH and coupling agents such as EDCI, HOBT and a base, to obtain the racemic compounds of formula 56.
Compounds useful in this invention are exemplified by the following preparative examples, which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art.